Variants of Uncertain Significance (VUS) can be challenging results for both the clinician and the laboratory geneticist, not to mention difficult to explain to the patient. An ongoing collaboration between the clinician and the laboratory provides the best chance for future reclassification of a variant. 

In my first blog, I discussed the steps of variant interpretation in order to understand how a geneticist ends up classifying a variant as a VUS. Now let’s look at the things clinicians can do to help lay the foundation for reclassification.

1) Does the patient have symptoms consistent with, and specific to, the disease caused by variants in the gene in question?

The healthy population has variants in each of their genes and most of these variations are benign. Therefore, a laboratory geneticist can’t classify a non-truncating variant as disease-causing based on the presence of a rare variant alone. If the patient’s phenotype is not consistent with, nor specific to, disease caused by that gene, it is very unlikely a novel VUS will be reclassified to likely pathogenic even after family member testing. For example, tall stature is consistent with, but not specific to, Marfan syndrome. However, tall stature, ectopia lentis, aortic root dilatation and arachnodactyly are consistent with and specific to Marfan syndrome.  Therefore, a novel de novo missense variant in FBN1 can be classified as likely pathogenic if the patient has aortic root dilatation or ectopia lentis in addition to the tall stature.

2) Would additional evaluation of the patient’s phenotype provide more information?

Some features of genetic conditions develop over time or may not be visible without specific investigations. As a clinician, sharing the evolution of your patient’s phenotype and the results of their investigations (even if negative) over time can be valuable information to share with the laboratory geneticist, especially if it becomes more specific to the gene in question. If a gene is associated with a specific clinical finding, additional testing should be considered to determine if that phenotype is present in the patient.

3) Would family member testing and segregation studies be helpful in reclassification of the VUS?

To answer this question, it is important to understand the most likely mode of inheritance in the family and the variant classification system used by your laboratory. Blueprint Genetics’ classification schemes for both autosomal dominant and recessive disorders follow the ACMG guidelines and are published on our website. It is important to keep in mind that testing only the parents or children (determining if the variant is de novo or determining phase) is not always sufficient to reclassify the VUS. Sometimes, multiple affected and unaffected family members are required with deep phenotyping on all individuals being tested.

4) Are there any recent publications about the variant in question?

New medical literature is constantly being published. Has the variant been reported in the scientific literature, ClinVar, or HGMD databases or other disease-related databases? A simple Google search of the variant can also be a powerful tool to identify publications that are sometimes not in these databases.

5) Are there researchers studying this gene who would be interested in a collaboration leading to functional studies?

GeneMatcher is a publicly accessible tool that can connect researchers and healthcare providers for just this purpose. You can also find connections based on matching the rare variant itself. Blueprint Genetics’ offers this no-cost service for VUS and LP variants via Connecting Clinicians in our online portal, Nucleus, regardless of whether the variant was identified by us or by another laboratory. This may contribute to the collective scientific knowledge and may provide evidence for variant reclassification if the same variant is seen in another patient with similar phenotype.

At Blueprint Genetics, if we identify additional patient(s) with the same variant and phenotype which provides further evidence for reclassification, we automatically issue a follow-up report with the updated classification for any patient found to have the same variant.

But lastly – it is important to realize that not all variants can be reclassified. VUSs have uncertain significance because we don’t have enough information to determine if they are disease-causing or not. There is still so much to discover about the human genome and diagnostics of rare inherited diseases, but the accumulating genetic knowledge is getting us closer to bringing more diagnoses to patients who need them.

Eija Seppälä is a senior geneticist at Blueprint Genetics.